Stilbene compounds comprising an adamantyl group, compositions and methods thereof

ABSTRACT

The invention relates to novel stilbene compounds having the general formula (I):  
                 
 
     as well as to pharmaceutical compositions for use in human or veterinary medicine, including dermatological, rheumatic, respiratory, cardiovascular and ophthalmic conditions and cosmetic compositions and methods of use thereof.

BACKGROUND OF THE INVENTION TECHNICAL FIELD OF THE INVENTION

[0001] The invention relates to stilbene compounds containing anadamantyl group which are novel and useful industrial products. Theinvention also relates to the use of these novel compounds inpharmaceutical compositions intended for use in human or veterinarymedicine, or alternatively, in cosmetic compositions.

SUMMARY OF THE INVENTION

[0002] The compounds according to the present invention have pronouncedactivity in the fields of cell proliferation and differentiation, andfind application more particularly in the topical and systemic treatmentof dermatological complaints associated with a keratinization disorder,dermatological (or other) complaints with an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations,whether benign or malignant. These compounds can also be used in thetreatment of degenerative diseases of connective tissue, to combat agingof the skin, both light-induced and chronological aging, and to treatcicatrization disorders. They also find application in the ophthalmicfield, in particular, in the treatment of corneopathies.

[0003] The compounds according to the present invention can also be usedin cosmetic compositions for body and hair hygiene.

[0004] The compounds according to the invention can be represented bythe general formula (I) below:

[0005] wherein:

[0006] R₁ represents

[0007] (i) the —CH₃ radical,

[0008] (ii) the radical —CH₂—O—R₆,

[0009] (iii) the radical —O—R₆, or

[0010] (iv) the radical —CO—R₇,

[0011] wherein the radicals R₆ and R₇ have the meanings given below,

[0012] Ar represents a radical of formulae (a) to (f) below:

[0013]  wherein R₈ and R₉ have the meanings given below,

[0014] R₂ and R₃ which may be identical or different, independentlyrepresent a hydrogen atom or a lower alkyl radical,

[0015] R₄ represents the radical —(X)_(m)—(CH₂)_(n)—Y—(CH₂)_(p)—R₁₀,

[0016] wherein the values m, n and P and the radicals X, Y and R₁₀having the meanings given below,

[0017] R₅ represents a hydrogen or halogen atom, a lower alkyl radicalor a radical —O—R₆,

[0018] R₆ represents a hydrogen atom, a lower alkyl radical or a radical—CO—R₁₁,

[0019] R₇ represents a hydrogen atom, a lower alkyl radical, a radical—OR₁₂ or a radical

[0020] wherein R′ and R″, which may be identical or different,independently represent a hydrogen atom, a lower alkyl radical, a mono-or polyhydroxyalkyl radical, an optionally substituted aryl radical oran amino acid or peptide or sugar residue, or alternatively, takentogether, form a heterocycle, it being understood that, in all of thetext hereinabove:

[0021] m is an integer ranging from 0 to 1,

[0022] n is an integer ranging from 1 to 6, inclusive,

[0023] p is an integer ranging from 1 to 6, inclusive,

[0024] X represents O or S(O)_(q),

[0025] Y represents O, S(O)_(q) or N—R₉,

[0026] g is an integer ranging from 0 to 2, inclusive,

[0027] R₈ represents a hydrogen or halogen atom, a lower alkyl radicalor a radical —O—R₆,

[0028] R₉ represents a hydrogen atom, a lower alkyl radical or a radical—CO—R₁₁,

[0029] R₁₀ represents a mono- or polyhydroxyalkyl radical wherein thehydroxyls are optionally protected in the form of methoxy, ethoxy,acetoxy or acetonide, a radical —CO—R₇ or an optionally substituted arylor aralkyl radical,

[0030] R₁₁ represents a lower alkyl radical,

[0031] R₁₂ represents a hydrogen atom, an alkyl radical, an alkenylradical, a mono- or polyhydroxyalkyl radical in which the hydroxyls areoptionally protected in the form of methoxy, ethoxy, acetoxy oracetonide, an optionally substituted aryl or aralkyl radical, a sugarresidue or an amino acid or peptide residue, and the optical andgeometrical isomers of the compounds of formula (I), as well as thesalts thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0032]FIG. 1 is a schematic diagram of a process for preparing thecompounds of formulae I(a), I(b) and I(c).

[0033]FIG. 2 is a schematic diagram of a process for preparing ahalogenated compound of the present invention.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

[0034] When the compounds according to the invention are in the form ofsalts resulting from the addition of an acid, the salts arepharmaceutically or cosmetically acceptable salts obtained by additionof an inorganic or organic acid, in particular, hydrochloric acid,sulfuric acid, acetic acid, citric acid, fumaric acid, hemisuccinicacid, maleic acid or mandelic acid. When the compounds according to theinvention are in the form of salts resulting from the addition of abase, those salts are preferably salts of an alkali metal or alkalineearth metal, or alternatively, salts of zinc or of an organic amine.

[0035] According to the present invention, the term alkyl radical isunderstood to refer to a linear or branched radical optionallysubstituted with one or more halogen atoms having from 1 to 20,preferably from 1 to 12, carbon atoms, advantageously the methyl, ethyl,isopropyl, butyl, tert-butyl, hexyl, nonyl and dodecyl radicals. When itis lower, the alkyl radical generally comprises from 1 to 10 carbonatoms, preferably from 1 to 6 carbon atoms. Exemplary lower alkylcomprise methyl, ethyl, propyl, isopropyl, tert-butyl and hexylradicals.

[0036] Exemplary linear alkyl radicals having from 1 to 20 carbon atomscomprise methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyland octadecyl radicals.

[0037] Exemplary branched alkyl radicals having from 1 to 20 carbonatoms comprise 2-methylpentyl, 1-methylhexyl and 3-methylheptylradicals.

[0038] By the term “alkenyl radical” is intended a linear or branchedradical having from 2 to 20 carbon atoms containing one or more doublebonds.

[0039] The preferred alkenyl radical is a radical ranging from 2 to 5carbon atoms and having one or more ethylenic unsaturations, morepreferably the allyl radical.

[0040] By the term “monohydroxyalkyl or polyhydroxyalkyl radical” isintended a radical containing from 1 to 6 carbon atoms and from 1 to 5hydroxyl groups.

[0041] The preferred monohydroxyalkyl radical comprises a radicalranging from 1 to 3 carbon atoms, in particular the hydroxymethyl,2-hydroxyethyl and 2-or 3-hydroxypropyl radicals.

[0042] The preferred polyhydroxyalkyl radical comprises a radical havingfrom 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, for example,the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.

[0043] The preferred aryl radical comprises a phenyl radical optionallysubstituted with at least one halogen atom, a hydroxyl radical, an alkylradical, a nitro function, a methoxy group or an optionally substitutedamine function.

[0044] The preferred aralkyl radical comprises the benzyl or phenethylradical optionally substituted with at least one halogen atom, ahydroxyl radical, a nitro function or a methoxy group.

[0045] By the term “sugar residue” is intended a residue derived inparticular from glucose, galactose or mannose, or alternatively fromglucuronic acid.

[0046] By the term “amino acid residue” is intended a residue derivedfrom one of the amino acids, for example, lysine, glycine or asparticacid, and by the term “peptide residue” is intended a dipeptide ortripeptide residue resulting from the combination of amino acids.

[0047] By the term “heterocycle” is intended a piperidino, morpholino,pyrrolidino or piperazino radical, optionally substituted in position 4with a C₁-C₆ alkyl or polyhydroxyalkyl radical as defined above.

[0048] When the radicals R₅ and R₈ represent a halogen atom, the halogenatom is preferably a fluorine, bromine or chlorine atom.

[0049] Particular compounds of formula (I) according to the presentinvention comprise:

[0050] Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethenyl]benzoate.

[0051]4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)ethenyl]benzoicacid.

[0052] Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]benzoate.

[0053]4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid.

[0054]4-[(Z)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid.

[0055] Methyl5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(E)-yl}pyridine-2-carboxylate.

[0056]5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}pyridine-2-carboxylicacid.

[0057]5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}pyridine-2-carboxylicacid.

[0058] Ethyl6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}nicotinate.

[0059]6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)yl}nicotinicacid.

[0060]6{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}nicotinicacid.

[0061] Methyl4-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(Z)-yl}-2-methoxybenzoate.

[0062]4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}-2-methoxybenzoicacid.

[0063]4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}-2-methoxybenzoicacid.

[0064] Ethyl4-{2-[3-adamant-1-yl-4-(3-ethoxymethoxypropyl)-phenyl]propen-(E/Z)-yl}benzoate.

[0065]4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]-propen-(E)-yl}benzoicacid.

[0066]4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]-propen-(Z)-yl}benzoicacid.

[0067] Ethyl4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/Z)-yl}benzoate.

[0068]4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(E)-yl}benzoicacid.

[0069]4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(Z)-yl}benzoicacid.

[0070] Ethyl4-{2-[3-adamant-1-yl-4-(3-diethylcarbamoyl-methoxypropyl)phenyl]propenyl}benzoate.

[0071]4-{2-[3-Adamant-1-yl-4-(3-diethylcarbamoylmethoxypropyl)phenyl]propenyl}benzoicacid.

[0072] Ethyl4-{2-[3-adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}benzoate.

[0073]4-{2-[3-Adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}benzoicacid.

[0074] Ethyl4-{2-[3-adamant-1-yl-4-(3-carbamoylmethoxy-propyl)phenyl]propenyl}benzoate.

[0075]4-{2-[3-Adamant-1-yl-4-(3-carbamoylmethoxypropyl)-phenyl]propenyl}benzoicacid.

[0076]N-Ethyl-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-l-propenyl]benzamide.

[0077]4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzamide.

[0078]N-4-(Hydroxyphenyl)-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzamide.

[0079]4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzenemethanol.

[0080] 4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzaldehyde.

[0081]4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]phenol.

[0082]4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid morpholide.

[0083]4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethyl-sulphanylphenyl)-1-propenyl]benzoicacid.

[0084] According to the present invention, the preferred compounds offormula (I) are those for which at least one, and more preferably all,of the conditions below apply:

[0085] R₁ is the radical —CO—R₇,

[0086] Ar represents the radicals of formula (a) or (b),

[0087] X and Y, which may be identical or different, independentlyrepresent oxygen or sulfur atoms,

[0088] R₃ represents a lower alkyl radical.

[0089] The subject of the present invention is also a process for thepreparation of the compounds of formula (I), in particular, according tothe reaction schemes set forth in FIGS. 1 and 2.

[0090] Thus, the compounds of formula I(a), I(b) and I(c) can beobtained (FIG. 1) by reacting, in an anhydrous medium in an organicsolvent, preferably THF, an aromatic aldehyde derivative (1) (when R₃ isa hydrogen atom) or an aromatic ketone derivative (2) (when R₃ is alower alkyl radical) in a Horner-Emmons or Wittig type reaction witharomatic phosphonate derivatives (3) or aromatic phosphine derivatives(4) in the presence of sodium hydride or potassium tert-butoxide.

[0091] In these olefination reactions, the geometrical isomer having anE configuration can also be obtained by conversion of the isomer, havinga Z configuration by irradiation under UV light.

[0092] When R₄ represents the radicals —(CH₂)_(n)—Y—(CH₂)_(p)—R₁₀, thecompounds can be obtained (FIG. 2) from phenol derivatives (5) which areconverted into triflate derivatives (6), followed by a reaction with atin derivative (7) in the presence of a palladium catalyst (for examplebis(-triphenyl-phosphine)palladium(II) chloride according to M.Echavarren and J. K. Stille, J. Am. Chem. Soc., 109, 5478-86 (1987)).The alcohol derivatives (9) are obtained by reaction of the ethylenicderivatives (8) with 9-borabicyclo[3.3.1]nonane, followed by oxidationwith aqueous hydrogen peroxide solution, according to E. F. Knights etal., J. Am. Chem. Soc., 90, 5281 (1968). By alkylation with ahalogenated derivative (10), the derivatives (11) are obtained. When R₁represents the —COOH radical, the compounds are prepared by protectingR₁ with a protecting group of the alkyl, allylic or tert-butyl type.Passage to the free form can be carried out:

[0093] in the case of an alkyl protecting group, using sodium hydroxideor lithium hydroxide in an alcoholic solvent, such as methanol, or inTHF,

[0094] in the case of an allylic protecting group, using a catalyst,such as certain transition metal complexes, in the presence of asecondary amine such as morpholine,

[0095] in the case of a protecting group of tert-butyl type, usingtrimethylsilyl iodide.

[0096] When R₁ is an alcohol radical, the compounds can be obtained fromthe acid by reduction in the presence of lithium aluminum hydride.

[0097] When R₁ is an aldehyde radical, the compounds can be obtainedfrom the alcohol by oxidation with manganese oxide or pyridiniumdichromate.

[0098] When R₁ is a radical of the amide type, the compounds can beprepared by conversion of the acid into the acid chloride, for example,with thionyl chloride, followed by reaction with aqueous ammonia or asuitable amine.

[0099] The products of general formula (I) can serve as startingmaterials for the manufacture of other compounds of formula (I)according to the invention. These compounds are obtained according tothe standard synthetic methods used in chemistry, such as thosedescribed in “Advanced Organic Chemistry” by J. March; John Wiley andSons (1985).

[0100] For example, functional modifications of the group R₁ can becarried out as indicated below: carboxylic acid → ester ester →carboxylic acid acid → acid chloride acid chloride → amide acid → amideacid → alcohol alcohol → aldehyde amide → amine thiol → thioetherthioether → sulfoxide thioether → sulfone sulfonic acid → sulfonic estersulfonic acid → sulfonamide sulfinic acid → sulfinic ester

[0101] The compounds according to the invention show activity in thetest of differentiation of mouse embryonic teratocarcinoma cells (F9)(Cancer Research, 43, 5268 (1983)) and/or in the test of inhibition ofornithine decarboxylase after induction with TPA in mice (CancerResearch, 38, 793-801 (1978)). These tests show the activities of thesecompounds in the fields of cell differentiation and cell proliferation,respectively. In the test of cell (F9) differentiation, an agonistactivity may be evaluated as an antagonist activity to retinoic acidreceptors. This is because an antagonist is inactive when it is alone inthis test, but partially or totally inhibits the effect produced by aretinoid which is an agonist towards the morphology and secretion of theplasminogen activator. Some of these compounds are thus also active in atest which is used to identify molecules which are RAR antagonists, asdescribed in French patent application No. 95/07302 filed on Jun. 19,1995 by the same Assignee as the present invention, which isincorporated by reference in its entirety herein. This test comprisesthe following steps: (i) a sufficient amount of an RAR-agonist moleculeis applied topically to a part of the skin of a mammal, (ii) a moleculecapable of exhibiting RAR-antagonist activity is administeredsystemically or topically to this same mammal or to this same part ofthe skin of the mammal, before, during or after step (i), and (iii) theresponse on that part of the mammal's skin which has been treated isevaluated. Thus, the response to a topical application, to the ear of amammal, of an RAR-agonist molecule, which corresponds to an increase inthe thickness of this ear, may be inhibited by the systemic or topicaladministration of an RAR-antagonist molecule. In addition, some of thesecompounds may provide synergism to the biological activity of productsbinding to the nuclear receptors.

[0102] The subject of the present invention is also, a pharmaceutical orcosmetic composition comprising the compounds of formula (I) as definedabove in combination with a pharmaceutically or cosmetically acceptablecarrier therefor.

[0103] The compounds according to the present invention are particularlyuseful in the following fields of treatment:

[0104] (1) for treating dermatological conditions associated with akeratinization disorder which has a bearing on cell differentiation andon proliferation, in particular for treating common acne, comedones,polymorphonuclear leucocytes, acne rosacea, nodulocystic acne, acneconglobata, senile acne and secondary acnes such as solar acne,medication-induced acne or occupational acne,

[0105] (2) for treating other types of keratinization disorders, inparticular ichthyosis, ichthyosiform states, Darrier's disease,palmoplantar keratoderma, leucoplasias and leucoplasiform states, andcutaneous or mucous (buccal) lichen,

[0106] (3) for treating other dermatological complaints associated witha keratinization disorder having an inflammatory and/or immunoallergiccomponent and, in particular, all forms of psoriasis, whether it iscutaneous, mucous or ungual psoriasis, and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema, or respiratory atopy oralternatively gingival hypertrophy; the compounds may also be used incertain inflammatory complaints which do not exhibit a disorder ofkeratinization,

[0107] (4) for treating all dermal or epidermal proliferations, whetherbenign or malignant and whether or not they are of viral origin, such ascommon warts, flat warts and verruciform epidermodysplasia, it beingalso possible for the oral or florid papillomatoses and theproliferations to be induced by ultraviolet radiation, in particular inthe case of basocellular and spinocellular epitheliomas,

[0108] (5) for treating other dermatological disorders such as bullosisand collagen diseases,

[0109] (6) for treating certain ophthalmological disorders, inparticular corneopathies,

[0110] (7) for repairing or combating both light-induced and chronologicaging of the skin or for reducing actinic keratoses and pigmentations,or any pathology associated with chronological or actinic ageing,

[0111] (8) for preventing or curing the stigmata of epidermal and/ordermal atrophy induced by local or systemic corticosteroids, or anyother form of skin atrophy,

[0112] (9) for preventing or treating cicatrization disorders or forpreventing or repairing stretch marks,

[0113] (10) for combating disorders of sebaceous functioning such as thehyperseborrhea of acne or simple seborrhea,

[0114] (11) in the treatment or prevention of cancerous or precancerousstates,

[0115] (12) in the treatment of inflammatory complaints such asarthritis,

[0116] (13) in the treatment of any complaint of viral origin on theskin or generally, such as Kaposi's syndrome,

[0117] (14) in the prevention or treatment of alopecia,

[0118] (15) in the treatment of dermatological or general complaintshaving an immunological component,

[0119] (16) in the treatment of complaints of the cardiovascular systemsuch as arteriosclerosis or hypertension, as well as insulin-independentdiabetes,

[0120] (17) in the treatment of skin disorders due to exposure to UVradiation.

[0121] In the therapeutic fields mentioned above, the compoundsaccording to the invention may advantageously be employed in combinationwith other compounds having retinoid-type activity, with D vitamins orderivatives thereof, with corticosteroids, with anti-free-radicalagents, a-hydroxy or a-keto acids or derivatives thereof, oralternatively with ion-channel blockers. The expression D vitamins orderivatives thereof is understood to refer, for example, to vitamin D2or D3 derivatives and in particular 1,25-dihydroxy vitamin D3. Theexpression anti-free-radical agent is understood to refer, for example,to α-tocopherol, superoxide dismutase, ubiquinol or certainmetal-chelating agents. The expression α-hydroxy or α-keto acids orderivatives thereof is understood to refer, for example, to lactic acid,malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid,glyceric acid or ascorbic acid or salts, amides or esters thereof.Lastly, the expression ion-channel blockers is understood to refer, forexample, to minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) andderivatives thereof.

[0122] The subject of the present invention is also a medicinalcomposition comprising at least one compound of formula (I) as definedabove, one of the optical or geometrical isomers thereof or one of thesalts thereof, in combination with a pharmaceutically or cosmeticallyacceptable carrier therefor.

[0123] The subject of the present invention is thus a novel medicinalcomposition intended in particular for treating the above-mentionedcomplaints, and which comprises, in a pharmaceutically acceptablesupport or carrier which is compatible with the mode of administrationselected for this composition, at least one compound of formula (I), oneof the optical or geometrical isomers thereof or one of the saltsthereof.

[0124] The compounds according to the invention may be administeredenterally, parenterally, topically or ocularly.

[0125] Via the enteral route, the medicinal products may be in the formof tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions,solutions, powders, granules, emulsions, microspheres or nanospheres orpolymeric or lipid vesicles which allow controlled release. Via theparenteral route, the compositions may be in the form of solutions orsuspensions for infusion or for injection.

[0126] The compounds according to the invention are generallyadministered at a daily dose of about 0.01 mg/kg to 100 mg/kg of bodyweight, taken in 1 to 3 doses.

[0127] Via the topical route, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended fortreating the skin and mucous membranes and may, in this case, be in theform of an ointment, cream, milk, salve, powder, impregnated pad,solution, gel, spray, lotion or suspension. They may also be in the formof microspheres or nanospheres or polymeric or lipid vesicles orpolymeric patches and hydrogels which allow controlled release. Thesetopical route compositions may moreover be either in anhydrous form orin an aqueous form, depending on the clinical indication.

[0128] Via the ocular route, they are primarily administered aseyedrops.

[0129] The compositions for topical or ocular use contain at least onecompound of formula (I) as defined above, or one of the optical orgeometrical isomers thereof, or alternatively one of the salts thereof,at a concentration preferably ranging from 0.001% to 5% by weightrelative to the total weight of the composition.

[0130] The compounds of formula (I) according to the invention also findan application in the cosmetics field, in particular, for body or hairhygiene and especially for treating skin types with a tendency towardsacne, for promoting the regrowth of hair, for combating hair loss, forcontrolling the greasy appearance of the skin or the hair, in protectingagainst the harmful effects of sunlight or in the treatment ofphysiologically dry skin types, and for preventing and/or combatinglight-induced or chronologic aging.

[0131] In the cosmetics field, the compounds according to the inventionmay also advantageously be employed in combination with other compoundshaving retinoid-type activity, with D vitamins or derivatives thereof,with corticosteroids, with anti-free-radical agents, α-hydroxy or α-ketoacids or derivatives thereof, or alternatively with ion-channelblockers, all of these different products being as defined above orhaving an art-recognized definition.

[0132] The present invention is thus also directed to a cosmeticcomposition which comprises, in a cosmetically acceptable support orcarrier which is suitable for topical application, at least one compoundof formula (I) as defined above, or one of the optical or geometricalisomers thereof or one of the salts thereof. The cosmetic composition ispreferably in the form of a cream, a milk, a lotion, a gel, microspheresor nanospheres or polymeric or lipid vesicles, a soap or a shampoo.

[0133] The concentration of compound of formula (I) in the cosmeticcomposition according to the present invention preferably ranges from0.001% to 3% by weight relative to the composition as a whole.

[0134] The medicinal and cosmetic compositions according to theinvention may also contain inert additives or even pharmacodynamicallyor cosmetically active additives or combinations of these additives and,in particular, wetting agents; depigmenting agents such as hydroquinone,azelaic acid, caffeic acid or kojic acid; emollients; moisturizingagents such as glycerol, PEG 400, thiamorpholinone and derivativesthereof, or, alternatively, urea; anti-seborrhea or anti-acne agentssuch as S-carboxymethylcysteine, S-benzylcysteamine, the salts and thederivatives thereof, or benzoyl peroxide; antibiotics such aserythromycin and esters thereof, neomycin, clindamycin and estersthereof, and tetracyclines; anti-fungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones; agents for promoting the regrowthof hair, such as minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide)and derivatives thereof, diazoxide(7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and phenytoin(5,4-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatoryagents; carotenoids and, in particular, β-carotene; anti-psoriaticagents such as anthraline and derivatives thereof and, lastly,eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-trynoic acid, theesters and the amides thereof.

[0135] The compositions according to the invention may also containflavor enhancing agents, preservatives such as para-hydroxybenzoic acidesters, stabilizing agents, moisture regulators, pH regulators, osmoticpressure modifiers, emulsifying agents, UV-A and UV-B screening agents,and antioxidants such as α-tocopherol, butylhydroxyanisole orbutylhydroxytoluene.

[0136] In order to further illustrate the present invention and theadvantages thereof, the following specific examples of the production ofactive compounds of formula (I) according to the invention, as well asvarious solid formulations based on such compounds are given, it beingunderstood that same are intended only as illustrative and in nowiselimitative.

[0137] A. EXAMPLES OF COMPOUNDS

EXAMPLE 1 Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethenyl]benzoate

[0138] (a) 3-(1-Adamantyl)-1-bromo-4-methoxyethoxymethoxy-benzene.

[0139] 3.8 g (0.13 mol) of sodium hydride (80% in oil) and 50 ml of DMFwere introduced into a three-necked flask under a stream of nitrogen. Asolution of 40.0 g (0.13 mol) of 2-(1-adamantyl)-4-bromophenol dissolvedin 100 ml of DMF was added dropwise and the mixture was stirred untilthe evolution of gas had ceased. A solution of 18 ml (0.15 mol) of2-methoxy-ethoxymethyl chloride in 20 ml of DMF was then added dropwiseand the mixture was stirred for four hours at room temperature. Thereaction medium was poured into water and extracted with ethyl ether.The organic phase was separated out after settling had taken place,washed with water, dried over magnesium sulfate and evaporated. Theresidue was purified by chromatography on a column of silica eluted witha mixture of dichloromethane and hexane (50/50). After evaporation ofthe solvents, 40.1 g (78%) of the expected product, with a melting pointof 69-70° C., was collected.

[0140] (b) 3-(1-Adamantyl)-4-methoxyethoxymethoxyphenyl-carboxaldehyde.

[0141] 34.0 g (89.0 mmol) of3-(1-adamantyl)-1-bromo-4-methoxyethoxymethoxybenzene and 250 ml of THFwere introduced into a three-necked flask under a stream of nitrogen. 43ml (106 mmol) of a solution of n-butyllithium (2.5M in hexane) was addeddropwise at −78° C. and the mixture was stirred for 30 minutes. 8.3 ml(106 mmol) of DMF was then added dropwise and the mixture was allowed towarm to room temperature. The reaction medium was poured into an aqueousammonium chloride solution and extracted with ethyl ether. The organicphase was separated out after settling had taken place, dried overmagnesium sulfate and evaporated. The residue obtained was purified bychromatography on a column of silica eluted with dichloromethane. Afterevaporation of the solvents, 17.6 g (58%) of the expected aldehyde, witha melting point of 63-64° C., was collected.

[0142] (c) Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethenyl]benzoate.

[0143] 360 mg (12 mmol) of sodium hydride (80% in oil) and 20 ml of THFwere introduced into a three-necked flask under a stream of nitrogen. Asolution of 70 ml of THF containing 3.44 g (10 mmol) of3-(1-adamantyl)-4-methoxyethoxymethoxyphenylcarbox-aldehyde, 3.6 g (12mmol) of diethyl 4-ethoxycarbonyl-benzylphosphonate and 440 mg of crownether (15-crown-5) were added dropwise. The reaction medium was stirredat room temperature for four hours and was then poured into water andextracted with ethyl ether. The organic phase was separated out aftersettling has taken place, dried over magnesium sulfate and evaporated.The residue obtained was triturated from hexane, filtered and dried.4.55 g (93%) of the expected ethyl ester, with a melting point of 87-88°C., was collected.

EXAMPLE 24-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)ethenyl]benzoicacid.

[0144] 2.0 g (4.0 mmol) of ethyl4-[(E)-2-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)ethenyl]-benzoateand methanolic sodium hydroxide solution (1.6 g of sodium hydroxide in50 ml of methanol) were introduced into a round-bottomed flask. Themixture was refluxed for four hours and evaporated to dryness, and theresidue was taken up in water and acidified to pH 1. The aqueous phasewas extracted with ethyl acetate and the organic phase was separated outafter settling had taken place, dried over magnesium sulfate andevaporated. The residue obtained was triturated from the minimum amountof ethyl ether, filtered and dried. 1.4 g (74%) of the expected acid,with a melting point of 207-208° C., was collected.

EXAMPLE 3 Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]benzoate

[0145] (a) 3-(1-Adamantyl)-4-methoxyethoxymethoxybenzoic acid

[0146] 3-(1-Adamantyl)-1-bromo-4-methoxyethoxy-methoxybenzene (28.5 g,72 mmol) was dissolved in 200 ml of THF. The solution obtained was addeddropwise onto magnesium (2.4 g, 100 mmol) and a crystal of iodine. Afterintroduction, the mixture was refluxed for two hours, cooled to −78° C.and a stream of CO₂ was passed through for one hour. The reaction mediumwas allowed to warm to room temperature and was then poured intosaturated aqueous ammonium chloride solution and extracted with ethylether. The organic phase was separated out after settling had takenplace, dried over magnesium sulfate and evaporated. The residue obtainedwas triturated from hexane, filtered and dried. 15.5 g (60%) of theexpected acid, with a melting point of 115-116° C., was collected.

[0147] (b) 3-(1-Adamantyl)-4-methoxyethoxymethoxyacetophenone

[0148] 15.5 g (43 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoicacid and 300 ml of anhydrous ethyl ether were introduced into athree-necked flask under a stream of nitrogen. 80 ml (0.13 mol) ofmethyllithium (1.6M in ether) was added dropwise at −20° C. and themixture was then stirred at room temperature for three hours. Thereaction medium was poured into saturated aqueous ammonium chloridesolution and the organic phase was separated out after settling hadtaken place, dried over magnesium sulfate and evaporated. 15.4 g (100%)of the expected acetophenone was collected in the form of a pale yellowoil.

[0149] (c) Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]benzoate

[0150] In a similar manner to Example 1(c), by reaction of 3.58 g (10mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyacetophenone with 3.13 g(12 mmol) of diethyl 4-ethoxycarbonylbenzylphosphonate, and afterchromatography on a column of silica eluted with a mixture of heptaneand ethyl acetate (90/10), 2.5 g (50%) of ethyl ester was obtained inthe form of a mixture of (E) and (Z) isomers.

EXAMPLE 44-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid

[0151] In a similar manner to Example 2, starting with 2.5 g (5 mmol) ofan (E/Z) mixture of ethyl4-[2-(3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)-1-propenyl]benzoateand after recrystallization from ethanol, 150 mg (13%) of4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)-1-propenyl]benzoicacid, with a melting point of 177-178° C., was collected.

EXAMPLE 54-[(Z)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid

[0152] The recrystallization filtrate obtained in Example 4 wasevaporated to dryness. The solid obtained was recrystallized fromethanol and, after filtration, 140 mg (12%) of4-[(Z)-2-(3-(1-adamantyl)-4-methoxy-ethoxymethoxyphenyl)-1-propenyl]benzoicacid, with a melting point of 198-199° C., was collected.

EXAMPLE 6 Methyl5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(E)-yl}pyridine-2-carboxylate

[0153] (a) 2-Bromo-5-methylpyridine

[0154] 500 ml of aqueous hydrobromic acid (47%) was mixed with 50.0 g(462 mmol) of 2-amino-5-methyl-pyridine in a two-liter reactor. Thesolution obtained was cooled to −20° C. and 206.9 g (1.3 mol) of brominewas then run in over ten minutes, while keeping the temperature between−15° C. and −25° C. The reaction, medium was stirred for one hour at−20° C., after which a solution composed of 82.7 g (1.2 mol) of sodiumnitrite dissolved in 300 ml of water was run in dropwise over twentyminutes.

[0155] The reaction medium was stirred for four hours at roomtemperature and was then cooled to −10° C., 800 ml of aqueous sodiumhydroxide solution (pH 10) was added and the mixture was stirred forfive minutes and extracted with ethyl ether. The organic phase wasseparated out after settling had taken place, washed with water and thenwith Na₂S₂O₃ solution, dried over magnesium sulfate and evaporated. 75.2g (94%) of the expected compound was collected in the form of orangecrystals with a melting point of 38-42° C.

[0156] (b) 2-Bromo-5-bromomethylpyridine

[0157] 10.0 g (58.0 mmol) of the bromo compound obtained in Example 4(a)and 70 ml of carbon tetrachloride were mixed together in a 250 mlthree-necked flask. The mixture was heated to about 35° C. and a groundmixture composed of 10.32 g (58.0 mmol) of N-bromosuccinimide and 421 mg(1.74 mmol) of benzoyl peroxide were introduced in a single portion. Thereaction medium was refluxed under light irradiation (1000 W) for threehours. The mixture was cooled and filtered, the filtrate was evaporatedto dryness, the residue was taken up in dichloromethane and washed withsaturated sodium bicarbonate solution and the organic phase was thendried over magnesium sulfate and evaporated. The residue obtained waspurified by chromatography on a column of silica eluted with a mixturecomposed of dichloromethane and heptane (1/1). After evaporation of thesolvents, 2.9 g (20%) of the expected compound was collected in the formof beige-colored crystals.

[0158] (c) Diethyl (6-bromopyrid-3-ylmethyl)phosphonate

[0159] 3.0 g (11.9 mmol) of the compound obtained in Example 6(b) and 10ml of triethyl phosphite were mixed together in a 100 ml round-bottomedflask. The mixture was refluxed for thirty minutes, cooled andevaporated to dryness. The residue obtained was purified bychromatography on a column of silica eluted with a mixture of ethylacetate and heptane (6/4). After evaporation of the solvents, 3.12 g(80%) of the expected compound was collected in the form of a paleyellow oil.

[0160] (d)5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}-2-bromopyridine

[0161] 2.6 g (8.4 mmol) of the compound obtained in Example 6(c), 5 mlof DMPU and 5 ml of THF were mixed together in a 100 ml round-bottomedflask. 250 mg (8.4 mmol) of 80% sodium hydride were added in a singleportion and the mixture was stirred at room temperature for thirtyminutes and then at 40° C. for fifteen minutes. A solution of 2.5 g (7.0mmol) of the ketone obtained in Example 3(b) dissolved in 10 ml of THFwas added dropwise. The reaction medium was stirred for four hours atroom temperature, after which saturated citric acid solution was added.The mixture was extracted with ethyl ether and the organic phase wasseparated out after settling had taken place, washed with water, driedover magnesium sulfate and evaporated. The residue obtained was purifiedby chromatography on a column of silica eluted with a mixture of ethylacetate and heptane (2/8). 2.69 g (75%) of the expected compound wascollected in the form of a yellow oil.

[0162] (e) Methyl5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(E)/(Z)-yl}pyridine-2-carboxylate

[0163] 4.1 g (8.0 mmol) of the bromo compound obtained in Example 6(d),890 mg (1.6 mmol) of 1,1′-bis(diphenylphosphino)ferrocene, 180 mg (0.8mmol) of palladium acetate, 20 ml of DMF, 2.23 ml (16.0 mmol) oftriethylamine and 3.24 ml (80 mmol) of methanol were introduced into ahydrogenation bomb. The reaction medium was confined under a pressure ofthree bar of carbon monoxide and heated at 100° C. for three hours. Themixture was cooled, taken up in water, extracted with ethyl acetate andwashed with water. The organic phase was then dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a column of silica eluted with a mixture of ethylacetate and heptane (2/8). After evaporation of the solvents, 1.3 g(33%) of the (Z) isomer in the form of a yellow oil and 1.16 g (29%) ofthe (E) isomer in the form of a pale yellow powder with a melting pointof 96-102° C. were collected.

EXAMPLE 75-{2-[3-Adamant-1-yl-4-(2-methoxyethoxlmethoxy)-phenyl]propen-(E)-yl}pyridine-2-carboxylicacid.

[0164] In a similar manner to Example 2, starting with 1.16 g (2.36mmol) of the (E) isomer of methyl5-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)phenyl]-propen-yl}pyridine-2-carboxylateobtained in Example 6(e), and after purification by trituration from amixture of ethyl ether and heptane (5/5), 0.98 g (86%) of5-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}pyridine-2-carboxylicacid was collected in the form of a beige-colored powder with a meltingpoint of 91-95° C.

EXAMPLE 85-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}pyridine-2-carboxylicacid.

[0165] In a similar manner to Example 2, starting with 1.30 g (2.64mmol) of the (Z) isomer of methyl5-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)phenyl]-propen-yl}pyridine-2-carboxylateobtained in Example 6(e), and after trituration from heptane, 1.05 g(83%) of5-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}pyridine-2-carboxylicacid was collected in the form of a white powder with a melting point of91-95° C.

EXAMPLE 9 Ethyl6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}nicotinate

[0166] (a) Ethyl 6-hydroxymethylnicotinate

[0167] 45.77 g (205 mmol) of ethyl 2,5-pyridine-dicarboxylate wasdissolved in 410 ml of absolute ethanol in a one-liter round-bottomedflask. The reaction medium was cooled to −5° C. and 5.04 g (133.2 mmol)of sodium borohydride was added, followed by portionwise addition of14.79 g (133.2 mmol) of calcium chloride, while keeping the temperaturebelow −5° C. The reaction medium was stirred at −5° C. for two hours andpoured into water. The product was extracted with ethyl ether and washedwith water and the organic phase was then dried over magnesium sulfateand evaporated. The residue obtained was purified by chromatography on acolumn of silica eluted with ethyl ether, in order to obtain 31.33 g(84%) of a white crystalline solid.

[0168] (b) Ethyl 6-bromomethylnicotinate

[0169] 10.0 g (55.2 mmol) of the compound obtained in Example 9(a), 36.6g (110 mmol)of carbon tetrabromide and 100 ml of ethyl ether weredissolved in a 500 ml round-bottomed flask. The reaction medium wascooled to 0° C. and 40.78 g (110 mmol) of trioctylphosphine was thenadded over ten minutes. The reaction medium was stirred for fifteenminutes at room temperature and poured into water. The product wasextracted with ethyl ether and washed with water and the organic phasewas then dried over magnesium sulfate and evaporated. The residueobtained was purified by chromatography on a column of silica elutedwith ethyl ether, in order to obtain 11.70 g (87%) of a red oil.

[0170] (c) Ethyl 6-(diethoxyphosphoryl)nicotinate

[0171] 11.0 g (45.0 mmol) of the compound obtained in Example 9(b) and100 ml of triethyl phosphite were mixed together in a 100 ml roundbottomed flask. The mixture was refluxed for five minutes, cooled andevaporated to dryness. The residue obtained was purified bychromatography on a column of silica eluted with a mixture of ethylacetate and heptane (8/2). After evaporation of the solvents, 9.7 g(71%) of the expected compound was collected in the form of a yellowoil.

[0172] (d) Ethyl6-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(E)-yl}nicotinate

[0173] 0.5 g (1.66 mmol) of the compound obtained in Example 9(c), 5 mlof DMPU and 5 ml of THF were mixed together in a 50 ml round-bottomedflask. 50 mg (1.66 mmol) of 80% sodium hydride was added in a singleportion and the mixture was stirred at room temperature for fifteenminutes and then at 40° C. for an additional fifteen minutes. A solutionof 496 mg (1.4 mmol) of the ketone obtained in Example 3(b) dissolved in5 ml of THF is added dropwise. The reaction medium was stirred for fourhours at room temperature, saturated citric acid solution was thenadded. The mixture was extracted with ethyl ether and the organic phasewas separated out after settling had taken place, washed with water,dried over magnesium sulfate and evaporated. The residue obtained waspurified by chromatography on a column of silica eluted with a mixtureof ethyl acetate and heptane (2/8). 60 mg (7%) of the expected (E)compound was collected in the form of a yellow solid with a meltingpoint of 78° C., along with a fraction corresponding to the (Z)compound, which would be directly reacted in order to obtain thecorresponding acid (Example 11).

EXAMPLE 106-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}nicotinicacid

[0174] In a similar manner to Example 2, starting with 1.30 g (2.57mmol) of the (E) isomer of ethyl6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-yl}nicotinateobtained in Example 9(d), and after purification by chromatography on acolumn of silica eluted with a mixture of ethyl acetate and heptane(5/5), 0.98 g (80%) of the expected compound was collected in the formof an off-white powder with a melting point of 86-90° C.

EXAMPLE 116-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}nicotinicacid.

[0175] In a similar manner to Example 2, starting with 463 mg (0.92mmol) of the (Z) isomer of ethyl6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propenyl}nicotinateobtained in Example 9(d), and after crystallization from a mixture ofethyl ether and heptane (5/5), 350 mg (80%) of the expected compound wascollected in the form of an off-white powder with a melting point of191-195° C.

EXAMPLE 12 Methyl4-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(Z)-yl}-2-methoxybenzoate

[0176] In a similar manner to Example 6(d), starting with 13.96 g (50.9mmol) of diethyl 4-methoxycarbonyl-benzylphosphonate and 9.13 g (25.45mmol) of the ketone obtained in Example 3(b), 8.25 g (62%) of the (Z)compound in the form of a white crystalline solid and 3.00 g (23%) ofthe (Z) compound in the form of a colorless oil were collected.

EXAMPLE 134-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenol]propen-(E)-yl}-2-methoxybenzoicacid.

[0177] In a similar manner to Example 2, starting with 3.00 g (5.76mmol) of the (E) isomer of methyl4-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)phenyl]-propen-yl}-2-methoxybenzoate obtained in Example 12, and aftercrystallization from methanol, 2.80 g (96%) of the expected compound wascollected in the form of yellow crystals.

EXAMPLE 144-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}-2-methoxybenzoicacid.

[0178] In a similar manner to Example 2, starting with 7.60 g (14.6mmol) of the (Z) isomer of methyl4-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-yl}-2-methoxybenzoateobtained in Example 12, and after crystallization from a mixture ofethyl ether and hexane (10/90), 7.39 g (100%) of the expected compoundwas collected in the form of white crystals with a melting point of 113°C.

EXAMPLE 15 Ethyl4-{2-[3-adamant-1-yl-4-(3-ethoxymethoxpropyl)-phenyl]propen-(E/Z)-yl}benzoate

[0179] (a) Methyl3-adamant-1-yl-4-trifluoromethane-sulphonyloxybenzoate.

[0180] 28.6 g (100.0 mmol) of methyl 3-(1-adamantyl)-4-hydroxybenzoatewas mixed with 122 mg (1.0 mmol) of N,N-dimethylaminopyridine, 200 ml ofdichloromethane and 28 ml of pyridine in a one liter three-necked flaskunder a nitrogen atmosphere. The mixture was cooled to −78° C. and 20.19ml (120.0 mmol) of triflic anhydride was added dropwise. The temperaturewas raised to room temperature and the mixture was continuously stirredfor two hours. The reaction medium was poured into 1N hydrochloric acidsolution, extracted with ethyl ether, washed with water, dried overmagnesium sulfate, filtered and evaporated to dryness. 41.5 g (99%) ofthe expected compound was collected in the form of a pale orange powderwith a melting point of 95° C.

[0181] (b) Methyl 3-adamant-1-yl-4-allylbenzoate

[0182] 23.06 g (55.1 mmol) of the compound obtained in Example 15(a) wasmixed with 4.66 g (110.0 mmol) of lithium chloride, 5.8 g (8.3 mmol) ofbis(triphenylphosphine)palladium(II) chloride, 21.89 g (66.0 mmol) ofallyltributyltin and 300 ml of N,N-dimethylformamide in a one literthree-necked flask under a nitrogen atmosphere. The mixture was heatedat 100° C. for two hours and was then poured into 1N hydrochloric acidsolution, extracted with ethyl ether, washed with water, dried overmagnesium sulfate, filtered and evaporated to dryness. The residueobtained was purified by distillation of tin salts (108-116° C. at8′10⁻² bar) followed by chromatography on a column of silica eluted withheptane. After evaporation of the solvents, 12.75 g (74%) of theexpected compound was collected in the form of a yellow oil.

[0183] (c) Methyl 3-adamant-1-yl-4-(3-hydroxypropyl)benzoate

[0184] 12.40 g (40.0 mmol) of the compound obtained in Example 15(b) wasdissolved in 250 ml of tetrahydrofuran in a 250 ml three-necked flaskunder a nitrogen atmosphere. The mixture was cooled to 0° C. and 240 ml(120.0 mmol) of 9-borabicyclo[3.3.1]nonane (9-BBN) was then run indropwise and the mixture was stirred at room temperature for two hours.The reaction medium was again cooled to 0° C. and 124 ml (124 mmol) ofaqueous sodium hydroxide solution (1M) was then run in dropwise,followed, while maintained at 0° C., by 102 ml (1 mol) of 30% aqueoushydrogen peroxide solution. The reaction medium was stirred for thirtyminutes at room temperature and was then poured into 1N hydrochloricacid solution, extracted-with ethyl ether, washed with water, dried overmagnesium sulfate, filtered and evaporated to dryness. The residue waspurified by chromatography on a column of silica eluted with a mixturecomposed of 30% ethyl acetate and 70% heptane. 9.4 g (71%) of theexpected compound were collected in the form of a white powder with amelting point of 77° C.

[0185] (d) Methyl 3-adamant-1-yl-4-(3-ethoxymethoxypropyl)-benzoate.

[0186] 8.00 g (24.3 mmol) of the compound obtained in Example 15(c) wasdissolved in 200 ml of toluene in a 500 ml three-necked flask under anitrogen atmosphere. 577 mg (1.7 mmol) of tetrabutylamine hydrogensulfate was added, the mixture was cooled to 0° C. and 6.78 ml (73.0mmol) of ethoxymethyl chloride and 120 ml of aqueous 10 M sodiumhydroxide were then run in dropwise. The reaction medium was stirred at0° C. for thirty minutes and then poured into 1N hydrochloric acidsolution, extracted with ethyl ether, washed with water, dried overmagnesium sulfate, filtered and evaporated to dryness. 9.39 g (100%) ofthe expected compound were collected in the form of a pale yellow oil.

[0187] (e) 3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)benzoic acid

[0188] In a similar manner to Example 2, starting with 9.39 g (24.3mmol) of the compound obtained in Example 15(d), 8.52 g (94%) of theexpected compound was collected in the form of a white powder with amelting point of 115° C.

[0189] (f) 1-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]-ethanone

[0190] In a similar manner to Example 3(b), starting with 8.00 g (21.5mmol) of the compound obtained in Example 15(e), 5.34 g (67%) of theexpected compound was collected in the form of a colorless oil.

[0191] (g) Ethyl4-{2-[3-adamant-1-yl-4-(3-ethoxymethoxy-propyl)phenyl]propen-(E/Z)-yl}benzoate

[0192] In a similar manner to Example 1(c), by reaction of 5.00 g (13.5mmol) of the compound obtained in Example 15(f) with 8.10 g (27.0 mmol)of diethyl 4-ethoxycarbonylbenzylphosphonate, and after chromatographyon a column of silica eluted with a mixture of heptane and ethyl acetate(90/10), 6.3 g (90%) of the ethyl ester was obtained in the form of amixture of (E) and (Z) isomers.

EXAMPLE 164-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxpropyl)-phenyl]propen-(E/Z)-yl}benzoicacids.

[0193] In a similar manner to Example,2, starting with 1.00 g (1.9 mmol)of the mixture of (E) and (Z) compounds obtained in Example 15(g), andafter chromatography on a column of silica eluted with a mixture ofheptane and ethyl acetate (80/20), 330 mg (34%) of the expected compound(Z isomer) in the form of a white powder with a melting point of 161°C., and 70 mg (7%) of the expected compound (E isomer) in the form of awhite powder with a melting point of 165° C., were collected.

EXAMPLE 17 Ethyl4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/Z)-yl}benzoate

[0194] (a) Ethyl4-{2-[3-adamant-1-yl-4-(3-hydroxypropyl)-phenyl]propen-(E/Z)-yl}benzoate

[0195] 5.00 g (9.68 mmol) of the compound obtained in Example 15(g) wasdissolved in 50 ml of absolute ethanol in a 250 ml three-necked flaskunder a nitrogen atmosphere. 5.18 ml (96.8 mmol) of concentratedsulfuric acid was added dropwise. The reaction medium was stirred atroom temperature for 24 hours and then at 40° C. for 5 hours, it waspoured into water, extracted with ethyl ether, washed with water, driedover magnesium sulfate, filtered and evaporated to dryness. 4.40 g (99%)of the expected compound was collected in the form of a pale yellow oil.

[0196] (b) Ethyl4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/Z)-yl}benzoate

[0197] In a similar manner to Example 15(d), starting with 1.00 g (2.18mmol) of the compound obtained in Example 17(a) and 0.78 ml (6.54 mmol)of benzyl bromide, 1.19 g (100%) of the expected compound was collectedin the form of a yellow oil.

EXAMPLE 184-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(E/Z)-yl}benzoicacids

[0198] In a similar manner to Example 2, starting with 1.00 g (1.82mmol) of the mixture of (E) and (Z) compounds obtained in Example 17(b), and after chromatography on a column of silica eluted with amixture of heptane and ethyl acetate (90/10), 480 mg (50%) of theexpected compound (Z isomer) in the form of a white powder with amelting point of 166° C., and 175 mg (18%) of the expected compound (Eisomer) in the form of a white powder with a melting point of 243° C.,were collected.

EXAMPLE 19 Ethyl4-{2-[3-adamant-1-yl-4-(3-diethylcarbamoyl-methoxypropyl)phenyl]propenyl}benzoate

[0199] In a similar manner to Example 15(d), starting with 1.00 g (2.18mmol) of the compound obtained in Example 17(a) and 0.83 ml (6.54 mmol)of N,N-diethylchloroacetamide, 1.00 g (80%) of the expected compound wascollected in the form of a pale yellow oil.

EXAMPLE 204-{2-[3-Adamant-1-yl-4-(3-diethylcarbamoylmethoxy-propyl)phenyl]propenyl}benzoicacid.

[0200] In a similar manner to Example 2, starting with 1.00 g (1.75mmol) of the mixture of (E) and (Z) compounds obtained in Example 19(a),and after chromatography on a column of silica eluted with a mixture ofheptane and ethyl acetate (90/10), 480 mg (50%) of the mixture (Z+E) ofthe expected compounds was collected.

EXAMPLE 21 Ethyl4-{2-[3-adamant-1-yl-4-(3-carboxymethoxy-propyl)phenyl]propenyl}benzoate

[0201] (a) Ethyl4-{2-[3-adamant-1-yl-4-(3-tert-butoxy-carbonylmethoxypropyl)phenyl]propenyl}benzoate

[0202] In a similar manner to Example 15(d), starting with 2.45 g (5.34mmol) of the compound obtained in Example 17(a) and 2.59 ml (16.0mmol)of tert-butyl bromoacetate, and after chromatography on a column ofsilica eluted with a mixture of heptane and ethyl acetate (90/10), 2.65g (86%) of the mixture (Z+E) of the expected compounds was collected inthe form of a colorless oil.

[0203] (b) Ethyl4-{2-[3-adamant-1-yl-4-(3-carboxymethoxy-propyl)phenyl]propenyl}benzoate

[0204] 2.60 g (4.54 mmol) of the compound obtained in Example 21(a) wasdissolved in 45 ml of dichloromethane in a 100 ml round-bottomed flaskunder a nitrogen atmosphere, and 3.50 ml (45.4 mmol) of trifluoroaceticacid was added dropwise. The reaction medium was stirred at roomtemperature for 16 hours and then at reflux for 8 hours. It was pouredinto water, extracted with dichloromethane, washed with water, driedover magnesium sulfate, filtered and evaporated to dryness. 2.35 g(100%) of the expected compound was collected in the form of a paleyellow oil.

EXAMPLE 224-{2-[3-Adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}benzoicacids

[0205] In a similar manner to Example 2, starting with 300 mg (0.60mmol) of the mixture of (E) and (Z) compounds obtained in Example 21(b),and after trituration from a mixture composed of 20% ethyl ether and 80%heptane, 150 mg (51%) of the mixture (Z+E) of the expected compounds wascollected.

EXAMPLE 23 Ethyl4-{2-[3-adamant-1-yl-4-(3-carbamoylmethoxy-propyl)phenyl]propenyl}benzoate

[0206] 1.00 g (1.93 mmol) of the compound obtained in Example 21(b) wasdissolved in 20 ml of dichloromethane in a 100 ml round-bottomed flaskunder a nitrogen atmosphere, and 0.42 ml (2.13 mmol) ofdicyclohexylamine was added dropwise. The reaction medium was stirred atroom temperature for five minutes, after which 0.14 ml (1.93 mmol) ofthionyl chloride was added dropwise and the mixture was stirred at roomtemperature for twenty minutes. The reaction medium was evaporated todryness, taken up in ethyl ether and filtered and the filtrate wasevaporated in order to obtain a yellow oil which was taken up in 10 mlof THF in order to obtain a solution. This solution was added dropwiseto a solution composed of 0.13 ml of 32% aqueous ammonia solution (2.13mmol) in 20 ml of THF and 0.32 ml (2.32 mmol) of triethylamine. Thereaction medium was stirred at room temperature for five minutes, pouredinto water and the pH was adjusted to 2 by addition of 0.5N HCl. Theproduct was extracted with ethyl ether, washed with water, dried overmagnesium sulfate, filtered and evaporated to dryness. Afterchromatography on a column of silica eluted with a mixture of heptaneand ethyl acetate (50/50), 650 mg (65%) of the mixture (Z+E) of theexpected compounds was collected.

EXAMPLE 244-{2-[3-Adamant-1-yl-4-(3-carbamoylmethoxypropyl)-phenyl]propenyl}benzoicacids

[0207] In a similar manner to Example 2, starting with 650 mg (1.26mmol) of the mixture of (E) and (Z) compounds obtained in Example 23,and after trituration from a mixture composed of 20% ethyl ether and 80%heptane, 340 mg (55%) of the mixture (Z+E) of the expected compounds wascollected.

EXAMPLE 25

[0208] The antagonist activity of the compounds of formula (I) wasevaluated in the mouse embryonic teratocarcinoma F9 cell differentiationtest (Cancer Research, 43, 5268 (1983)).

[0209] These compounds tested at 10⁻⁶ M were inactive as agonists inthis test and partially or totally inhibit the effect produced by anagonist retinoid on the morphology and secretion of the plasminogenactivator, according to the following procedure.

[0210] The F9 cells were inoculated in 12-well clusters, the compoundswere tested at from 10⁻⁹ to 10⁻⁵ M in the presence of all-trans-retinoicacid or of a synthetic agonist retinoid,4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylaminomethyl)benzoicacid (CD 2043), at 10⁻⁸ M. After incubation for three days, themorphological observations were carried out and the concentration of thetest compound which inhibits the agonist effect on the secretion of theplasminogen activator by 50% (IC50) was determined. Antagonist againstCD 2043 (10 nM) F9 differentiation test Example No. IC50 (nM) 2 310 4 95 630 10 35 7 600

[0211] B. FORMULATION EXAMPLES

[0212] (1) ORAL ROUTE

[0213] (a) The following composition was prepared in the form of a 0.8 gtablet: Compound of Example 1 0.005 g Pregelatinized starch 0.265 gMicrocrystalline cellulose 0.300 g Lactose 0.200 g Magnesium stearate0.030 g

[0214] For the treatment of acne, 1 to 3 tablets will be administered toan adult individual each day for 3 to 6 months depending on the severityof the case being treated.

[0215] (b) A drinkable suspension intended to be packaged in 5 mlampules is prepared: Compound of Example 2 0.050 g Glycerol 0.500 g 70%Sorbitol 0.500 g Sodium saccharinate 0.010 g Methyl parahydroxybenzoate0.040 g Flavoring qs Purified water qs 5 ml

[0216] For the treatment of acne, 1 ampule will be administered to anadult individual each day for 3 months depending on the severity of thecase being treated.

[0217] (c) The following formulation intended to be packaged in gelatincapsules is prepared: Compound of Example 4 0.025 g Corn starch 0.060 gLactose qs 0.300 g

[0218] The gelatin capsules used consist of gelatin, titanium oxide anda preservative. In the treatment of psoriasis, 1 gelatin capsule will beadministered to an adult individual each day for 30 days.

[0219] 2) TOPICAL ROUTE

[0220] (a) The following nonionic water-in-oil cream is prepared:Compound of Example 1 0.100 g Mixture of emulsifying lanolin 39.900 galcohols, waxes and refined oils, having the trademark “AnhydrousEucerin”, by BDF Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100.000 g

[0221] This cream will be applied to psoriatic skin once or twice a dayfor 30 days.

[0222] (b) A gel is prepared by making the following formulation:Compound of Example 3 0.050 g Base erythromycin 4.000 gButylhydroxytoluene 0.050 g Hydroxypropylcellulose having the 2.000 gtrademark “Klucel HF” by Hercules Ethanol (95%) qs 100.000 g

[0223] This gel will be applied to skin affected with dermatitis or toacneic skin 1 to 3 times each day for 6 to 12 weeks depending on theseverity of the case being treated.

[0224] (c) An antiseborrheic lotion is prepared by mixing together thefollowing ingredients: Compound of Example 20.030 g Propylene glycol5.000 g Butylhydroxytoluene 0.100 g Ethanol (95%) qs 100.000 g

[0225] This lotion will be applied twice each day to a seborrheic scalpand a significant improvement is observed within a period of 2 to 6weeks.

[0226] (d) A cosmetic composition to combat the harmful effects of thesun is prepared by mixing together the following ingredients: Compoundof Example 12 1.000 g Benzylidene camphor 4.000 g Fatty acidtriglycerides 31.000 g  Glyceryl monostearate 6.000 g Stearic acid 2.000g Cetyl alcohol 1.200 g Lanolin 4.000 g Preservative 0.300 g Propyleneglycol 2.000 g Triethanolamine 0.500 g Fragrance 0.400 g Demineralizedwater qs 100.000 g 

[0227] This composition will be applied daily and makes it possible tocombat light-induced aging.

[0228] (e) The following nonionic oil-in-water cream is prepared:Compound of Example 14 0.500 g Vitamin D3 0.020 g Cetyl alcohol 4.000 gGlyceryl monostearate 2.500 g PEG 50 stearate 2.500 g Karite butter9.200 g Propylene glycol 2.000 g Methyl parahydroxybenzoate 0.075 gPropyl parahydroxybenzoate 0.075 g Sterile demineralized water qs100.000 g 

[0229] This cream will be applied to psoriatic skin once or twice eachday for 30 days.

[0230] (f) A topical gel is prepared by mixing together the followingingredients: Compound of Example 18 0.050 g Ethanol 43.000 g α-Tocopherol 0.050 g Carboxyvinyl polymer, trademark 0.500 g “Carbopol941” by Goodrich Triethanolamine as an aqueous 3.800 g solutioncontaining 20% by weight Water 9.300 g Propylene glycol qs 100.000 g 

[0231] This gel will be applied in the treatment of acne 1 to 3 timeseach day for 6 to 12 weeks depending on the severity of the case beingtreated.

[0232] (g) A lotion for preventing hair loss and for promoting hairregrowth is prepared by mixing together the following ingredients:Compound of Example 15 0.05 g Minoxidil 1.00 g Propylene glycol 20.00 gEthanol 34.92 g Polyethylene glycol having a 40.00 g molecular weight of400 Butylhydroxyanisole 0.01 g Butylhydroxytoluene 0.02 g Water qs100.00 g

[0233] This lotion will be applied twice a day for 3 months to a scalpwhich has lost a considerable amount of hair.

[0234] (h) An anti-acne cream is prepared by mixing together thefollowing ingredients: Compound of Example 5 0.050 g Retinoic acid 0.010g Mixture of glyceryl stearates and 15.000 g polyethylene glycol (75mol), having the trademark “Gelot 64” by Gattefosse Polyoxyethylenatedkernel oil 8.000 g containing 6 mol of ethylene oxide, having thetrademark “Labrafil M2130 CS” by Gattefosse Perhydrosqualene 10.000 gPreservatives qs Polyethylene glycol having a 8.000 g molecular weightof 400 Disodium salt of 0.050 g ethylenediaminetetra-acetic acidPurified water qs 100.000 g

[0235] This cream will be applied to skin affected with dermatitis or toacneic skin 1 to 3 times each day for 6 to 12 weeks.

[0236] (i) An oil-in-water cream is prepared by making the followingformulation: Compound of Example 20 0.020 g Betamethasone 17-valerate0.050 g S-Carboxymethylcysteine 3.000 g Polyoxyethylene stearate (40 molof 4.000 g ethylene oxide) having the trademark “Myrj 52” by AtlasSorbitan monolaurate 1.800 g polyoxyethylenated with 20 mol of ethyleneoxide, having the trademark “Tween 20” by Atlas Mixture of glycerylmono- and 4.200 g distearate, having the trademark “Géléol” byGattefosse Propylene glycol 10.000 g Butylhydroxyanisole 0.010 gButylhydroxytoluene 0.020 g Cetostearyl alcohol 6.200 g Preservatives qsPerhydrosqualene 18.000 g Mixture of caprylic/capric 4.000 gtriglycerides, having the trademark “Miglyol 812” by Dynamit NobelTriethanolamine (99% by weight) 2.500 g Water qs 100.000 g

[0237] This cream will be applied twice a day to skin affected withdermatitis, for 30 days.

[0238] (j) The following cream of oil-in-water type is prepared: Lacticacid 5.000 g Compound of Example 23 0.020 g Polyoxyethylene stearate (40mol of 4.000 g ethylene oxide), having the trademark “Myrj 52” by AtlasSorbitan monolaurate 1.800 g polyoxyethylenated with 20 mol of ethyleneoxide, having the trademark “Tween 20” by Atlas Mixture of glycerylmono- and 4.200 g distearate, having the trademark “Geleol” byGattefosse Propylene glycol 10.000 g Butylhydroxyanisole 0.010 gButylhydroxytoluene 0.020 g Cetostearyl alcohol 6.200 g Preservatives qsPerhydrosqualene 18.000 g Mixture of caprylic/capric 4.000 gtriglycerides, having the trademark “Miglyol 812” by Dynamit Nobel Waterqs 100.000 g

[0239] This cream will be applied once a day and helps to combat aging,both light-induced and chronologic aging.

[0240] While the invention has been described in terms of variouspreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A stilbene compound, corresponding to formula(I):

wherein: R₁ represents (i) the —CH₃ radical, (ii) the radical —CH₂—O-R₆,(iii) the radical —O—R₆, or (iv) the radical —CO—R₇, wherein theradicals R₆ and R₇ having the meanings given below, Ar represents aradical comprising one of the radicals of formulae (a) to (f):

wherein R₈ and R₉ having the meanings given below, R₂ and R₃, which maybe identical or different, represent a hydrogen atom or a lower alkylradical, R₄ represents the radical —(X)_(m)—(CH₂)_(n)—Y—(CH₂)_(p)—R₁₀the values m, n and p and the radicals X, Y and R₁₀ having the meaningsgiven below, R₅ represents a hydrogen or halogen atom, a lower alkylradical or a radical —O—R₆, R₆ represents a hydrogen atom, a lower alkylradical or a radical —CO—R₁₁, R₇ represents a hydrogen atom, a loweralkyl radical, a radical —OR₁₂ or a radical

wherein R′ and R″, which may be identical or different, represent ahydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkylradical, an optionally substituted aryl radical or an amino acid orpeptide or sugar residue, or alternatively, taken together, form aheterocycle, wherein m is an integer equal to 0 or 1 n is an integerranging from 1 to 6, inclusive, p is an integer ranging from 1 to 6,inclusive, X represents O or S(O)_(q), Y represents O, S(O)_(q) or N—R₉,q is an integer ranging from 0 to 2, inclusive, R₈ represents a hydrogenor halogen atom, a lower alkyl radical or a radical —O—R₆, R₉ representsa hydrogen atom, a lower alkyl radical or a radical —CO—R₁₁, R₁₀represents a mono- or polyhydroxyalkyl radical wherein the hydroxyls areoptionally protected in the form of methoxy, ethoxy, acetoxy oracetonide, a radical —CO—R₇ or an optionally substituted aryl or aralkylradical, R₁₁ represents a lower alkyl radical, R₁₂ represents a hydrogenatom, an alkyl radical, an alkenyl radical, a mono- or polyhydroxyalkylradical in which the hydroxyls are optionally protected in the form ofmethoxy, ethoxy, acetoxy or acetonide, an optionally substituted aryl oraralkyl radical, a sugar residue or an amino acid or peptide residue, orsalts thereof or optical or geometrical isomers thereof.
 2. The compoundas defined by claim 1, which is in the form of a salt of an alkali metalor alkaline earth metal, of zinc, of an organic amine or of an inorganicor organic acid.
 3. The compounds as defined by claim 1, wherein thelower alkyl radical comprises a methyl, ethyl, propyl, isopropyl,tert-butyl or hexyl radical.
 4. The compound as defined by claim 1,wherein the polyhydroxyalkyl radical comprises 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl, or 2,3,4,5-tetrahydroxypentyl radical or thepentaerythritol residue.
 5. The compound as defined by claim 1, whereinthe aryl radical comprises a phenyl radical optionally substituted withat least one halogen atom, a hydroxyl radical, an alkyl radical, a nitrofunction, a methoxy group or an optionally substituted amine function.6. The compound as defined by claim 1, wherein the aralkyl radicalcomprises benzyl or phenethyl radicals, optionally substituted with atleast one halogen atom, a hydroxyl, a nitro function or a methoxy group.7. The compound as defined by claim 1, wherein the alkenyl radicalcomprises radicals containing from 2 to 5 carbon atoms and having one ormore ethylenic unsaturations, and in particular the allyl radical. 8.The compound as defined by claim 7, wherein the alkenyl radicalcomprises an allyl radical.
 9. The compound as defined by claim 1,wherein the sugar residue comprises a glucose, galactose, mannose orglucuronic acid residue.
 10. The compound as defined by claim 1, whereinthe amino acid residue comprises a residue derived from lysine, glycineor aspartic acid.
 11. The compound as defined by claim 1, wherein thepeptide residue comprises dipeptide or tripeptide residues.
 12. Thecompound as defined by claim 1, wherein the heterocyclic radicalcomprises piperidino, morpholino, pyrrolidino and piperazino radicalsoptionally substituted in position 4 with a C₁-C₆ alkyl orpolyhydroxyalkyl radical.
 13. The compound as defined by claim 1,wherein the halogen atom comprises fluorine, bromine or chlorine. 14.The compound as defined by claim 1, comprising: Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethenyl]benzoate;4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)ethenyl]benzoicacid; Ethyl4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]benzoate;4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid;4-[(Z)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid; Methyl5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(E)-yl}pyridine-2-carboxylate;5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}pyridine-2-carboxylicacid;5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}pyridine-2-carboxylicacid; Ethyl6-{2-[3-adamant-1-yl-4-(2-methoxy-ethoxymethoxy)phenyl]propen-(E)-yl}nicotinate;6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}nicotinicacid;6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}nicotinicacid; Methyl4-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(Z)-yl}-2-methoxybenzoate;4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}-2-methoxybenzoicacid;4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}-2-methoxybenzoicacid; Ethyl4-{2-[3-adamant-1-yl-4-(3-ethoxy-methoxypropyl)phenyl]propen-(E/Z)-yl}benzoate;4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxy-propyl)phenyl]propen-(E)-yl}benzoicacid;4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]propen-(Z)-yl}benzoicacid; Ethyl4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/Z)-yl}-benzoate;4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(E)-yl}-benzoicacid;4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(Z)-yl}benzoicacid; Ethyl4-{2-[3-adamant-1-yl-4-(3-diethylcarbamoyl-methoxypropyl)phenyl]propenyl}benzoate;4-{2-[3-Adamant-1-yl-4-(3-diethylcarbamoylmethoxy-propyl)phenyl]propenyl}benzoicacid; Ethyl4-{2-[3-adamant-1-yl-4-(3-carboxymethoxypropyl)phenyl]propenyl}benzoate;4-{2-[3-Adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}benzoicacid; Ethyl4-{2-[3-adamant-1-yl-4-(3-carbamoylmethoxy-propyl)phenyl]propenyl}benzoate;4-{2-[3-Adamant-1-yl-4-(3-carbamoylmethoxypropyl)-phenyl]propenyl}benzoicacid;N-Ethyl-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]benzamide;4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzamide;N-4-(Hydroxyphenyl)-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)-1-propenyl]benzamide;4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzenemethanol;4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzaldehyde;4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]phenol;4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoicacid morpholide; or4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethyl-sulphanylphenyl)-1-propenyl]benzoicacid; or mixtures thereof.
 15. The compound as defined by claim 1,having at least one of the following characteristics: R₁ is the radical—CO—R₇, Ar represents the radicals of formulae (a) or (b), X and Y,which may be identical or different, independently represent an oxygenor sulfur atom, R₃ represents a lower alkyl radical.
 16. Apharmaceutical composition comprising at least one stilbene compound asdefined by claim 1 and pharmaceutically acceptable carrier therefor. 17.The pharmaceutical composition as defined by claim 16, wherein saidstilbene compound ranges from 0.01% to 5% by weight relative to theweight of the entire composition.
 18. A cosmetic composition comprisingat least one stilbene compound as defined by claim 1 and a cosmeticallyacceptable carrier therefor.
 19. The cosmetic composition as defined byclaim 18, wherein said stilbene compound ranges from 0.001% to 3% byweight relative to the weight of the entire composition.
 20. Thecosmetic composition as defined by claim 18, which is applied to thebody or the hair.
 21. A method for the prevention or treatment of adermatological condition at least one compound as defined by claim 1, toa patient in need of such prevention or treatment.
 22. The method asdefined by claim 21, wherein said dermatological condition comprises acondition involving at least one of common acne, comedones,polymorphonuclear leukocytes, acne rosacea, nodulocystic acne, acneconglobata, senile acne, secondary acnes, medication-induced acne,occupational acne, ichthyosis, ichthyosiform states, Darrier's disease,palmoplantar keratoderma, leucoplasia, a leucoplasiform state, cutaneousor mucous (buccal) lichen, keratinization disorder having aninflammatory and/or immunoallergic component, cutaneous, mucous orungual psoriasis, psoriatic rheumatism, cutaneous atopy, eczema,respiratory atopy, gingival hypertrophy; inflammatory complaints whichdo not exhibit a disorder of keratinization; dermal or epidermalproliferations, common warts, flat warts and verruciformepidermodysplasia, oral or florid papillomatoses, basocellular andspinocellular epitheliomas; bullosis and collagen diseases;ophthalmological disorders, corneopathies; light-induced andchronological aging of the skin, actinic keratoses and pigmentations;stigmata of epidermal and/or dermal atrophy induced by local or systemiccorticosteroids, skin atrophy; cicatrization disorders, stretch marks;sebaceous functioning, hyperseborrhoea of acne or simple seborrhoea;cancerous or precancerous states, promyelocytic leukemias; inflammatorycomplaints, arthritis; viruses; alopecia; dermatological complaintshaving an immunological component; complaints of the cardiovascularsystem, arteriosclerosis, hypertension, insulin-independent diabetes; orskin disorders due to exposure to UV radiation.